Chagas'disease, highly prevalent throughout Latin America, is a serious and debilitating infection caused by the parasite Trypanosoma cruzi that results in severe cardiomyopathy or megasyndromes. Due to the significant drug resistance, toxicity and low efficacy associated with the current therapies, benznidazole and nifurtimox, new medicines are critically needed. The Sandler Center at UCSF has recently developed a new high-throughput screening (HTS) assay to screen chemotherapeutic agents for efficacy against the intracellular pathogenic stage of T. cruzi. In response to NIAID RFA-AI-09-034 partnerships with product development, we propose to support collaboration between the Genome Institute of the Novartis Foundation (GNF), the Sandler Center and the Small Molecule Discovery Center (SMDC) at UCSF to meet several of the research goals and objectives of this initiative in neglected tropical diseases. The three centers possess excellent preclinical drug discovery programs and capabilities, including extensive compound libraries. We propose to run an HTS campaign utilizing this newly developed T. cruzi assay to identify potential chemotypes for medicinal chemistry lead optimization. From chemotypes identified, we will select at least two chemotype series that possess lead-like properties for further development using an iterative medicinal chemistry lead optimization strategy. This strategy will combine in vitro testing of compound efficacy and drug-like characteristics (ADMET) with assessment of in vivo pharmacokinetic and efficacy properties to continually guide further medicinal chemistry efforts. We anticipate that at the end of the grant period we will have identified one to three fully optimized candidates with good efficacy, pharmacokinetic and toxicity profiles for further translational development as potential drugs to treat Chagas'disease. Project Narrative: New drugs to treat the neglected tropical disease Chagas', caused by infections of the Trypanosoma cruzi parasite, are urgently required. For this grant, we propose to utilize a novel Trypanosoma cruzi High Throughput Screening assay developed at UCSF to screen a large high quality library available from GNF (Genomic Institute of the Novartis Foundation), and jointly UCSF and GNF will use leads from this screen to embark on a full medicinal chemistry lead optimization program. At the end of the grant period we anticipate having 1-3 fully optimized clinical candidates with good efficacy, pharmacokinetic and toxicity profiles that are poised to enter into IND-enabling studies to prepare for initiating human clinical trials.